Cocaine and other psychoactive drugs are highly addictive and cocaine abuse represents a major health, social and economical problem. We have demonstrated that Drosophila melanogaster, a powerful genetic model system, can be used in the study of drug responsiveness. My data show that circadian modulation of the dopamine system in the Drosophila nervous system is dependent on the period protein (per). Since modulation of biogenic amines is implicated in the drug responsiveness, sensitization to cocaine was tested in perO mutant flies. Although their sensitivity to cocaine is normal, they are unable to sensitize to repeated exposures. To learn the roles that circadian genes play in drug responsiveness the dependence of sensitization on the abundance of PER protein will be undertaken using different transgenic lines and other circadian mutants. Second, the relationship between PER and tyramine in the process of sensitization to cocaine using HPLC measurements, enzyme activity assays and transgenic flies will be investigated. A working model is that per might be involved in development of sensitization by modulating the level of tyramine.